In recent years tissue plasminogen activator (t-PA) has emerged as an interesting therapeutic alternative to conventional thrombolytic agents, streptokinase (SK) and urokinase (UK). The major physiological plasminogen activator, t-PA, in contrast to UK and SK, activates fluid phase circulating plasminogen inefficiently but activates fibrin-associated plasminogen very efficiently. The relative advantage of t-PA over SK and UK is best explained in the context of a brief outline of the current knowledge of the fibrinolytic enzyme system provided in the following.
FIG. 1 is a simplified scheme of the fibrinolytic enzyme system consisting of plasminogen activators, one or more plasminogen activator inhibitors (PA), the proenzyme plasminogen, the active serine protease plasmin and plasmin inhibitors. The physiological plasminogen activators t-PA and UK synthesized in and secreted by endothelial cells are inhibited by one, perhaps two, newly discovered fast acting inhibitors. One of these proteins has been purified to homogeneity and characterized in several laboratories. This plasminogen activator inhibitor is found in plasma at varying concentrations and found in platelets at high concentrations and released during platelet activation as the thrombotic process evolves. It is found in sharply increased concentrations during the third trimester of pregnancy, in patients with thromboembolism, and in patients with conditions predisposing to thromboembolic disease. Thus, different patients with different levels of plasminogen activator inhibitor may respond differently to infused t-PA or UK. All plasminogen activators act on plasminogen producing plasmin which is a nonspecific trypsin-like protease which proteolytically degrades, in addition to fibrin, several plasma clotting factors. Plasmin is counterbalanced by a major inhibitor, alpha-two plasmin inhibitor and to a lesser degree by alpha-two macroglobulin. FIG. 1 depicts the fundamental differences between the commercially available thrombolytic agents SK and UK and t-PA. SK and UK activate plasminogen adsorbed to the thrombus as well as plasma plasminogen, and the activation of plasma plasminogen results in temporary hyperplasminemia and a profound coagulation defect. The coagulation defect arises because plasmin proteolytically degrades and destroys clotting factors V and VIII as well as fibrinogen. The degradation products of fibrinogen add to the coagulation defect since these fibrinogen fragments possess potent anti-coagulant properties. In contrast, t-PA is relatively fibrin-specific. When administered at moderate doses, it activates only thrombus plasminogen and not plasma plasminogen to any significant extent. However, when given rapidly at high doses, t-PA may cause temporary systemic hyperplasminemia and a mild to moderately severe fibrinolytic coagulation defect. Intravenously administered t-PA has been shown effective in dissolving experimental venous and arterial clots in animals. In a recent preliminiary report from a large prospective controlled clinical trial, t-PA administered intravenously was shown to be effective in establishing reperfusion of occluded coronary arteries in patients with acute myocardial infarction.